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MP4 Remuxer.Mp3 Isolated … … ….demo Version. No Registration.WinZip Commander 3.0.One of the most important challenges in therapeutic angiogenesis is the identification of biomarkers that are able to predict the clinical outcomes. Thus, the overall goal of this proposal is to identify novel biomarkers for drug-resistance in angiogenesis. In Phase I studies, we will investigate a candidate biomarker CDKN2B/p15INK4B, a member of the p16 family of cell cycle regulators with unknown function in endothelial cells. We propose that CDKN2B/p15INK4B is involved in the development of angiogenic resistance. First, CDKN2B/p15INK4B gene-deleted embryonic stem cells are specifically able to form angiogenic blood vessels in their vicinity. Second, the interaction of CDKN2B/p15INK4B with members of the TGF-beta signaling pathway is necessary for the inhibition of angiogenesis. In this pathway, CDKN2B/p15INK4B is associated with Smad and Smad-independent pathways and regulates TGF-beta mediated effects in endothelial cells and in a transgenic mouse model of angiogenesis. Third, CDKN2B/p15INK4B gene-deleted mice display increased blood vessel formation and inflammation in various organs, and develop proteinuria and glomerulonephritis associated with a phenotype that resembles the human disease, Alport Syndrome. Based on these preliminary data, we hypothesize that loss of CDKN2B/p15INK4B expression in the blood vessels confers an angiogenic resistant phenotype and that levels of CDKN2B/p15INK4B expression in endothelial cells could serve as a biomarker to predict response to anti-angiogenic therapy. To validate CDKN2B/p15INK4B as a biomarker of anti-angiogenic resistance and drug efficacy in clinical angiogenesis trials, we propose the following Specific Aims:
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